title: Bone-derived stem cells repair the heart after myocardial infarction through transdifferentiation and paracrine signaling mechanisms.
abstract: BACKGROUND
  Autologous bone marrow-derived or cardiac-derived stem cell therapy for heart disease has demonstrated safety and efficacy in clinical trials, but functional improvements have been limited. Finding the optimal stem cell type best suited for cardiac regeneration is the key toward improving clinical outcomes.
  
  
  OBJECTIVE
  To determine the mechanism by which novel bone-derived stem cells support the injured heart.
  
  
  RESULTS
  Cortical bone-derived stem cells (CBSCs) and cardiac-derived stem cells were isolated from enhanced green fluorescent protein (EGFP+) transgenic mice and were shown to express c-kit and Sca-1 as well as 8 paracrine factors involved in cardioprotection, angiogenesis, and stem cell function. Wild-type C57BL/6 mice underwent sham operation (n=21) or myocardial infarction with injection of CBSCs (n=67), cardiac-derived stem cells (n=36), or saline (n=60). Cardiac function was monitored using echocardiography. Only 2/8 paracrine factors were detected in EGFP+ CBSCs in vivo (basic fibroblast growth factor and vascular endothelial growth factor), and this expression was associated with increased neovascularization of the infarct border zone. CBSC therapy improved survival, cardiac function, regional strain, attenuated remodeling, and decreased infarct size relative to cardiac-derived stem cells- or saline-treated myocardial infarction controls. By 6 weeks, EGFP+ cardiomyocytes, vascular smooth muscle, and endothelial cells could be identified in CBSC-treated, but not in cardiac-derived stem cells-treated, animals. EGFP+ CBSC-derived isolated myocytes were smaller and more frequently mononucleated, but were functionally indistinguishable from EGFP- myocytes.
  
  
  CONCLUSIONS
  CBSCs improve survival, cardiac function, and attenuate remodeling through the following 2 mechanisms: (1) secretion of proangiogenic factors that stimulate endogenous neovascularization, and (2) differentiation into functional adult myocytes and vascular cells.
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Duran
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Makarewich
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Sharp
authors.forename: Timothy
authors.initials: T
authors.lastname: Starosta
authors.forename: Fang
authors.initials: F
authors.lastname: Zhu
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Hoffman
authors.forename: Yumi
authors.initials: Y
authors.lastname: Chiba
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
authors.forename: Remus M
authors.initials: RM
authors.lastname: Berretta
authors.forename: Hajime
authors.initials: H
authors.lastname: Kubo
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
mesh_terms: D042501:Angiogenic Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis / Q000235:genetics; D015415:Biomarkers; D001842:Bone and Bones / Q000166:cytology*; D054338:Cell Transdifferentiation; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology* / Q000637:transplantation; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000166:cytology*; D018919:Neovascularization, Physiologic / Q000235:genetics; D019899:Paracrine Communication / Q000502:physiology*; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000235:genetics; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D042501:Angiogenic Proteins; D000950:Antigens, Ly; D015415:Biomarkers; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D019009:Proto-Oncogene Proteins c-kit
keywords: differentiation; myocardial infarction; neovascularization; paracrine communication; stem cells